Pristimerin attenuates spasmolytic polypeptide-expressing metaplasia via p57 (Cdkn1c)-mediated glycolytic reprogramming: A metabolic avenue for gastric cancer prevention

Abstract

Gastric cancer is a malignancy with high mortality globally, and spasmolytic polypeptide-expressing metaplasia (SPEM), a critical precancerous lesion in gastric carcinogenesis, represents a crucial target for early intervention to halt malignant progression. Pristimerin is a natural triterpenoid compound that primarily induces apoptosis and cell cycle arrest, and inhibits tumor cell migration and invasion by suppressing signaling pathways, such as nuclear factor kappa-B, phosphatidylinositol 3-kinase/protein kinase B, and mitogen-activated protein kinase. This opinion review provides an in-depth understanding of recent studies, exploring the therapeutic effects of pristimerin on SPEM and its underlying molecular mechanism. A recent study innovatively revealed that pristimerin effectively reverses tamoxifen-induced damage to the gastric mucosa and the SPEM phenotype by modulating Cdkn1c (p57)-mediated glycolytic reprogramming. This finding not only offers a novel perspective on the role of metabolic reprogramming in precancerous gastric lesions but also highlights targeting the “p57-glycolysis” axis as a potential therapeutic strategy for preventing gastric cancer. As a naturally derived bioactive agent, pristimerin has promising potential for clinical translation.

Key Words: Spasmolytic polypeptide-expressing metaplasia; Gastric precancerous lesion; Cdkn1c (p57); Pristimerin; Glycolytic reprogramming

Core Tip: This opinion review discusses evidence that the natural compound pristimerin reverses spasmolytic polypeptide-expressing metaplasia (SPEM) not only by alleviating high-dose tamoxifen-induced gastric mucosal injury and oxyntic atrophy, but also by restoring parietal and chief cell lineages and suppressing aberrant proliferation. The study further identifies Cdkn1c (p57) as a key metabolic checkpoint: p57 is downregulated during SPEM, upregulated following pristimerin treatment, and required for the compound’s antiglycolytic and anti-SPEM effects in gastric organoids.

INTRODUCTION

Gastric cancer remains one of the leading causes of cancer-related death worldwide, particularly in East Asia, Eastern Europe, and parts of Latin America[1-4]. Despite advances in endoscopic surveillance, surgical techniques, and systemic therapy, most patients are still diagnosed at advanced stages, when curative options are limited and the prognosis is poor[5,6]. Consequently, growing attention has shifted from treating established gastric cancer to intercepting disease earlier in its natural history at the stage of precancerous lesions. Among these, spasmolytic polypeptide-expressing metaplasia (SPEM) has emerged as a key precursor state within the gastric carcinogenic cascade[7-9].

SPEM is a metaplastic lesion that arises in the gastric body glands. Currently recognized triggers primarily include drug or chemical induced injury, Helicobacter pylori (H. pylori) infection, autoimmune gastritis, inflammatory cytokines, and metabolic or microenvironmental factors[10-13]. Its core features include the trans-differentiation of chief cells, acquisition of a mucous neck cell-like phenotype[14,15], and expression of trefoil factor 2 (TFF2), also known as spasmolytic polypeptide. This lesion is considered a reactive metaplasia that arises in response to oxyntic atrophy and chronic injury[16,17]. Increasing evidence suggests that SPEM is not merely a benign adaptive response but may represent a precursor state that promotes progression to intestinal metaplasia, dysplasia, and ultimately gastric carcinoma, particularly in the setting of chronic inflammation or persistent injury[16,18,19]. Therefore, understanding the mechanisms that drive SPEM development and maintenance, as well as its therapeutic vulnerabilities, is critical for designing rational strategies to prevent gastric cancer.

In this context, the study highlighted in this editorial explores a compelling and relatively underappreciated aspect of SPEM biology: Metabolic reprogramming, particularly glycolysis, and its therapeutic modulation by the natural compound pristimerin[20-22]. The authors further identify a role for Cdkn1c (p57), a cyclin-dependent kinase inhibitor, in linking metabolic alterations to SPEM progression. Their findings suggest the existence of a “p57-glycolysis” axis that can be targeted by pristimerin to halt or reverse SPEM-associated changes.

PRISTIMERIN EFFECTIVELY REVERSES THE SPEM PATHOLOGICAL PROCESS

Numerous studies have demonstrated that high-dose tamoxifen (HDT) induces acute gastric chief cell injury and lineage reprogramming in mice[23-25]. Following HDT treatment, the mouse gastric mucosa exhibited typical SPEM features, including glandular structure disorganization, significant oxyntic gland atrophy, decreased chief cell numbers, and the appearance of extensive metaplastic epithelium expressing spasmolytic polypeptide-associated markers.

Many results demonstrated that compared with the SPEM model group treated solely with HDT, the group receiving pristimerin therapy exhibited multiple improvements[26]. First, overall structural damage to the gastric mucosa was alleviated, with a more regular glandular arrangement; mucosal layer thickness and glandular integrity were significantly greater in the pristimerin-treated group than in the HDT model group. Second, the degree of oxyntic gland atrophy was reduced, with glandular lumina and basal structures more completely preserved, suggesting recovery of secretory units. The extent of glandular hyperplasia and metaplastic foci associated with SPEM decreased. When combined with histological scoring, these findings demonstrated that pristimerin significantly reduced the pathological score of SPEM. These findings indicate that pristimerin reversed HDT-induced SPEM progression rather than merely attenuating inflammation or mildly mitigating tissue damage.

Of particular note, pristimerin ameliorated oxyntic atrophy, which is a precursor to long-term impairment of gastric acid secretion. The persistent loss of acid-secreting parietal cells (oxyntic cells) and their supporting oxyntic glands is believed to create a microenvironment favorable for neoplastic transformation[17,27]. By reversing oxyntic atrophy, pristimerin may help prevent a cascade of pathological events triggered by persistent hypochlorhydria or achlorhydria, including bacterial overgrowth, chronic inflammation, and epigenetic alterations.

The study also revealed that pristimerin could ameliorate SPEM-associated oxyntic atrophy. This finding holds potential significance for preventing long-term impairment of gastric acid secretion and the cascade of pathological changes it can trigger. In terms of overall efficacy, pristimerin demonstrated promising disease-reversing ability at the animal level: It not only mitigated acute injury but also halted or delayed the sustained progression of SPEM.

MULTITARGET REVERSAL OF SPEM CHARACTERISTICS

With its multi-target, multi-pathway antitumor mechanisms, broad-spectrum antitumor activity, and ability to reverse drug resistance and enhance chemosensitivity, pristimerin has shown great advantages in cancer prevention and treatment[28,29]. SPEM is characterized by a set of relatively specific molecular markers, such as TFF2, WFDC2, AQP5, CD44v9 and MUC6, which reflect the metaplastic shift of gastric fundic gland chief cells toward a lineage resembling pyloric gland/neck mucus cells[16,30-33]. Additionally, molecules such as WFDC2 are associated with malignant potential and poor prognosis in the gastric mucosa and are frequently significantly upregulated in SPEM and progressive lesions[34,35]. Studies have shown that in the HDT-induced mouse SPEM model, the expression of these SPEM-related markers is dramatically increased. However, following pristimerin treatment, the expression levels of these molecules are significantly reduced, suggesting that the degree of metaplasia is effectively suppressed.

On the other hand, SPEM and gastric precancerous lesions are often accompanied by an enhanced stem cell-like phenotype, including abnormal upregulation of stem cell markers such as Lgr5 and Troy. These markers indicate increased self-renewal and regenerative potential of mucosal cells, which also implies a greater risk of malignant transformation[36,37]. H. pylori can directly colonize the base of gastric glands, activating and expanding Lgr5⁺ stem cells. The persistent chronic inflammation and immune response following infection play a critical role in the malignant progression from SPEM to intestinal metaplasia, dysplasia, and eventually adenocarcinoma. SPEM cells upregulate WFDC2 and CD44v9. These molecules recruit M2 macrophages to the injury site, and M2 macrophages in turn upregulate interleukin-33[38]. Pristimerin treatment not only downregulates SPEM marker molecules but also significantly suppresses the expression of stem cell-related factors such as Lgr5 and Troy[23,39,40]. These findings indicate that pristimerin can block or attenuate the tendency of the gastric mucosa to shift toward a cancer stem cell-like state.

Furthermore, the proliferation marker Ki67 is often highly expressed in SPEM and precancerous lesions, reflecting a state of high proliferation and turnover in lesional areas[41]. Research has also demonstrated that pristimerin significantly reduces Ki67 expression and inhibits the increase in both the number and size of organoids in an in vitro model. This further confirms its substantial inhibitory effect on aberrant proliferation.

TARGETING GLYCOLYTIC REPROGRAMMING

In precancerous lesions and tumors, glycolytic reprogramming is considered a critical survival strategy adopted by cells to adapt to harsh microenvironments[42-45]. Under sustained metabolic reprogramming and intestinalization signals, gastric stem cells, especially those located in the gastric isthmus, accumulate mutations and eventually undergo malignant transformation. During the gastric precancerous process, chronic inflammation leads to the death of acid-secreting parietal cells and changes in cellular differentiation, ultimately resulting in SPEM[46]. At the same time, in gastric cancer, cancer cells need to maintain a high level of glycolysis rather than generating energy through oxidative phosphorylation[47]. In the SPEM model, multiple components of the glycolytic pathway are abnormally activated: Upstream regulators such as hypoxia inducible factor-1α are upregulated[48,49], key rate-limiting enzymes, including pyruvate kinase M2 and lactate dehydrogenase A, are increased, and lactate production is elevated[50,51]. Together, these changes constitute a typical hyperglycolytic phenotype. Cells in this state exhibit stronger proliferative capacity and are more likely to alter their surrounding microenvironment to evade immune surveillance.

The impact of pristimerin on this metabolic state was significant. In SPEM mice, tamoxifen-treated GES-1 cells, and N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)/H. pylori-induced gastric organoids, pristimerin consistently downregulated the expression of the aforementioned glycolytic-related molecules and reduced overall glycolytic pathway activity, albeit to varying degrees. At the cellular level, addition of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG)[52] partially reversed SPEM-like phenotypes even in the absence of pristimerin. Furthermore, pristimerin and 2-DG synergistically inhibited glycolysis and ameliorated the SPEM phenotype, confirming that their mechanism of action is closely linked to regulation of the glycolytic pathway. These findings suggest that glycolytic reprogramming itself is a key driver of SPEM formation and maintenance[53]. Thus, SPEM is not merely a lineage-specific metaplastic process but is also accompanied by significant glycolytic reprogramming. By inhibiting the reprogramming process, pristimerin shifts lesional cells from a high-glycolysis high-proliferation-high-stress malignant metabolic state back toward a level more similar to homeostasis, thereby mitigating the pathological progression of SPEM[54].

p57 FUNCTIONS AS THE KEY NODE FOR BRIDGING THERAPY AND METABOLIC REPROGRAMMING

Cdkn1c (p57), a member of the cyclin-dependent kinase inhibitor protein/kinase inhibited protein family of cyclin-dependent kinase inhibitors, governs the G1-S transition and cellular homeostasis. In addition to the classic tumor-suppressive role of p57, its downregulation has been linked to poor prognosis in multiple malignancies[55-58]. In addition, it modulates energy metabolism by balancing glycolysis and oxidative phosphorylation[59].

In gastric SPEM models (HDT-induced mice and MNNG/H. pylori organoids), p57 expression is markedly reduced at the oxyntic gland base, a niche rich in chief/stem cells. Pristimerin treatment restored p57 expression at this site, paralleling the observed pathological improvement. Functional studies confirm that p57 is an essential mediator: P57 overexpression mimicked the antiglycolytic and anti-SPEM effects of pristimerin, whereas p57 knockdown abolished these effects. Thus, p57 is not merely a correlative biomarker but a functional nexus that integrates cell-cycle control, metabolic reprogramming, and lineage fate. Restoring p57 expression may block chief-cell progression from regenerative reserve toward metaplasia preneoplasia-malignancy[26,60].

CONCLUSION

In conclusion, this study provides compelling evidence that pristimerin is a promising candidate for SPEM intervention, demonstrating a true reversal of SPEM progression rather than a nonspecific anti-inflammatory or cytoprotective response. Pristimerin attenuates the metaplastic features and stem-like characteristics that underlie malignant risk by downregulating SPEM markers. Crucially, Cdkn1c (p57) has emerged as the central hub linking pristimerin, metabolism, and phenotype, establishing the “pristimerin-p57-glycolysis axis” as a novel and rational target for the metabolic chemoprevention of gastric cancer (Figure 1), thereby providing both theoretical and experimental evidence for the intervention of early gastric lesions.

Figure 1 Schematic illustration of the mechanism by which pristimerin inhibits spasmolytic polypeptide-expressing metaplasia. Pristimerin inhibits glycolytic reprogramming and ameliorates spasmolytic polypeptide-expressing metaplasia via p57 pathway-mediated downregulation of hypoxia inducible factor-1α, pyruvate kinase M2, and lactate dehydrogenase A. HIF-1α: Hypoxia inducible factor-1α; PKM2: Pyruvate kinase M2; LDHA: Lactate dehydrogenase A; SPEM: Spasmolytic polypeptide-expressing metaplasia.